Congenital heart disease represents the most common form of human birth defect, occurring in nearly 1 in 100 live births. An increasing number of patients with these defects are surviving infancy. Approximately one-third of congenital heart defects involve malformations of the outflow tract. Related defects are found in isolation and as part of common human syndromes. Our laboratory has investigated mechanisms of cardiac morphogenesis with particular attention to outflow tract formation. During cardiogenesis, neural crest cells interact with second heart field myocardium and endocardial cushion mesenchyme. Our recent work demonstrates that Jagged1/Notch signaling within the second heart field initiates a signaling cascade involving Fgf8, Bmp4, and downstream effectors that modulate outflow tract development and aortic arch artery patterning. Hence, complex tissue–tissue interactions and integration of multiple pathways converge to orchestrate proper patterning of the outflow region. The role of Notch signaling in adult cardiac homeostasis and disease is an area of active investigation.